Genetically modified human umbilical cord perivascular cells for prophylaxis against or treatment of biological or chemical agents

Abstract

The invention provides methods of preventing or treating diseases or disorders caused by biological agents or chemical agents in a subject (e.g., a mammal, such as a human) by administering genetically modified human umbilical cord perivascular cells.

The invention claimed is: 
     
       1. A method for treating or protecting a human subject exposed to a chemical agent comprising administering to the subject a composition comprising an isolated cell population comprising human umbilical cord perivascular cells (HUCPVCs) having a 3G5+, CD45−, CD44+ phenotype,
 wherein the cell population is characterized by rapid proliferation and the presence of human progenitor cells, and the HUCPVCs in said cell population are genetically modified to express a butyrylcholinesterase (BChE) polypeptide or to increase the expression of an endogenous butyrylcholinesterase (BChE) polypeptide, and 
 wherein said composition treats or protects said subject exposed to said chemical agent. 
 
     
     
       2. The method of  claim 1 , wherein said HUCPVCs are allogeneic or xenogeneic to said subject. 
     
     
       3. The method of  claim 1 , wherein said chemical agent is selected from a nerve agent, a vesicant, a blood agent, and a respiratory agent. 
     
     
       4. The method of  claim 1 , wherein said chemical agent is selected from nitrogen mustards, sulfur mustards, acetylcholinesterase inhibitors, Lewisites, saxitoxin, bis(2-chloroethyl)ethylamine, 2-chlorovinyldichloroarsine, 2-chloroethylchloromethylsulfide, bis(2-chloroethyl)sulfide, sarin (GB), cyclosarin (GF), soman (GD), tabun (GA), VX, amiton, PFIB, 3-quinuclidinyl benzilate, phosgene, diphosgene, cyanogens chloride, hydrogen cyanide, and chloropicrin. 
     
     
       5. The method of  claim 1 , wherein said subject has been exposed to said chemical agent prior to said administering. 
     
     
       6. The method of  claim 1 , wherein said HUCPVCs are genetically modified to express two or more oligonucleotides or polypeptides. 
     
     
       7. The method of  claim 1  further comprising administering one or more therapeutic agents to said subject, wherein said therapeutic agent enhances or prolongs a prophylactic or therapeutic benefit provided upon administration of said isolated cell population comprising HUCPVCs to said subject. 
     
     
       8. The method of  claim 7 , wherein said therapeutic agent is a cytokine, antiviral agent, immunostimulant, or immunosuppressant. 
     
     
       9. The method of  claim 1 , wherein said composition comprises a pharmaceutically acceptable carrier or excipient. 
     
     
       10. The method of  claim 1 , wherein said HUCPVCs are genetically modified to express an RNA interference (RNAi) oligonucleotide capable of inhibiting viral replication or infection. 
     
     
       11. The method of  claim 10 , wherein said RNAi oligonucleotide is a small inhibitory RNA (siRNA) or short hairpin RNA (shRNA) molecule. 
     
     
       12. The method of  claim 1 , wherein said HUCPVCs are genetically modified to express a polypeptide selected from an antibody, an antibody fragment, a microbial antigen, a cytokine or growth factor, a hormone, a clotting factor, a drug resistance or anti-viral resistance polypeptide, an anti-venom agent, an antioxidant, a receptor or ligand, an immunomodulatory factor, a detectable label, and a cellular factor. 
     
     
       13. The method of  claim 12 , wherein said antibody or antibody fragment is a single chain antibody (scFv), Fab, Fab′2, scFv, SMTP, diabody, nanobody, aptamer, or domain antibody;
 said cytokine or growth factor is selected from tumor necrosis factor alpha (TNF-α), TNF-β, interferon-alpha (IFN-α), IFN-β, IFN-γ, interleukin 1 (IL-1), IL-1β, interleukin 2-14, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), RANTES, MIP-1α), transforming growth factor-beta (TGF-β), platelet derived growth factor (PGDF), insulin-like growth factor (IGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), erythropoietin (EPO), and thrombopoietin (TPO); 
 said hormone is selected from angiotensinogen, angiotensin, parathyroid hormone (PTH), basic fibroblast growth factor-2, luteinizing hormone, follicle-stimulating hormone, adrenocorticotrophic hormone (ACTH), vasopressin, oxytocin, somatostatin, gastrin, cholecystokinin, leptin, atrial-natriuretic peptide, epinephrine, norephinephrine, dopamine, calcitonin, and insulin; 
 said clotting factor is selected from factor VII, factor VIII, factor IX, and fibrinogen; 
 said enzyme is selected from adenosine deaminase, glucocerebrosidase, alpha-1 antitrypsin, a viral thymidine kinase, hypoxanthine phosphoribosyl transferase, manganese superoxide dismutase (Mn-SOD), catalase, copper-zinc-superoxide dismutase (CuZn-SOD), extracellular superoxide dismutase (EC-SOD), glutathione reductase, phenylalanine hydroxylase, nitric oxide synthetase, and paraoxinase; 
 said receptor or ligand is selected from a T-cell receptor (TCR), a LDL receptor, surface-bound immunoglobulin, soluble CD4, cystic fibrosis transmembrane conductance receptor (CFTR), and a F C  receptor; 
 said immunomodulatory factor is selected from CTLA-4, VCP, PLIF, LSF-1, Nip, CD200, uromodulin, CD40L (CD154), FasL, CD27L, CD30L, 4-1BBL, CD28, CD25, B7.1, B7.2, and OX40L; 
 said detectable label is green fluorescent protein (GFP); or 
 said cellular factor is selected from cytochrome b, ApoE, ApoC, ApoAI, MDR, tissue plasminogen activator (tPA), urokinase, hirudin, β-globin, α-globin, HbA, ras, src, and bd. 
 
     
     
       14. The method of  claim 1 , wherein said subject is administered said composition prior to exposure to said chemical agent. 
     
     
       15. The method of  claim 3 , wherein said chemical agent is a nerve agent. 
     
     
       16. The method of  claim 15 , wherein said nerve agent is sarin (GB), cyclosarin (GF), soman (GD), tabun (GA), VX, or amiton.